Preparation of tetrahydropyrimidines



United States Patent ABSTRACT OF THE DISCLCSURE A process for'preparing tetrahydropyrimidines comprising reacting ,B-cyanoethyl aliphatic amines with an acylating agent, hydrogenating the N-acyl- N-B-cyanoethyl aliphatic amine to produce acyl-N-aliphatic-1,3- propanediamine, and bringing about closure of a 6 membered ring by heating the diamine in the presence of a metal catalyst or the salts thereof. The ring closure is especially satisfactory when conducted in the presence of nickel, copper, cobalt, manganese, platinum, palladium and the chloride, bromide, iodide, oxide, sulfate, carbonate, and acetate salts thereof, in the presence of a strong base at a temperature of about 170-230 C.

CROSS-REFERENCE TO RELATED APPLICATION This application is a continuation-in-part of our prior application Ser. No. 328,194, filed Dec. 5, 1963, now abandoned.

BACKGROUND OF THE INVENTION (1) Field of the invention This invention relates to a process for the production of tetrahydropyrimidines by a three step process:

( 1) Acylating a fl-cyanoet-hyl aliphatic amine, then (2) Catalytic hydrogenation to form acyl-N-aliphatic- 1,3-propanediamine, and

(3) Catalytic ring closure to yield 3-aliphatic-2-substituted-3,4,5,6-tetrahydropyrimidine.

(2) Description of the prior art Prior art methods of forming 2-substituted tetrahydropyrimidines have been the reaction of a monocarboxylic acid and a 1,3-propane diamine at temperatures within the range of '0-300 C. to produce cyclization. The lower temperature of about 250 C. has been utilized for ring closure when a chemical dehydrating agent has been employed. Even with the rigorous reaction conditions, these reactions required long periods of time.

3 aliphatic-Z-substituted tetrahydropyrimidines have been formed by heating equal moles of acetic acid and a N aliphatic 1,3-propanediamine at high temperatures to form the amide and then heating at about 250-300 C. and with a dehydrating agent to cyclize the monoamide to form the tetrahydropyrimidine. This reaction, even with the rigorous reaction conditions, results in low product yield due to the formation of diamide and difiiculty in ring closure of the monoamide which is formed.

SUMMARY preparations. A further object is to provide an improved process for the preparation of 3-aliphatic, 2-aliphatic or aromatic, 3,4,5,6-tetrahydropyrimidines and intermediates thereof through the formation of the acylated diamines and the use of metal catalysts for ring closure.

Other specific objects and advantages will appear as the specification proceeds.

In one embodiment of our invention, we react a ,9- cyanoethylaliphatic amine having from 8 to 22 carbon atoms which may be a straight or branched chain, saturated or unsaturated, with an aliphatic or aromatic acylating agent, such as an acid halide or acid anhydride, and then hydrogenating the resulting N-acyl-N-fl-cyaiioethyl amine over 'a nickel catalyst in the presence of a base. The resulting acyl-N-alkyl-1,3-propanediamine is then heated to yield the tetrahydropyrimidine product. In the final step, the acyl-N-alkyl-1,3-propanediamine may be distilled, preferably in vacuo, at a temperature of about -230" C. in the presence of 'a metal catalyst, such a nickel, copper, cobalt, manganese, platinum, palladium, and salts thereof, and preferably in the presence of a strong base selected from the group of potassium hydroxide, sodium hydroxide, calcium hydroxide, etc. Particularly useful catalysts may be selected from the group consisting of nickel, copper, cobalt, manganese, platinum, palladium, and the chloride, bromide, iodide, oxide, sulfate, carbonate, and acetate salts thereof. From about 0.5 to 5 weight percent catalyst is preferrred. The use of the catalysts has been found to be extremely effective in bringing about ring closure.

By way of illustration, the following specific example may be set out in detail, the example dealing with the preparation of 3 dodecyl-2-methyl-3,4,5,6-tetrahydropyrimidine, and the sequence reactions being set out as follows:

(1) B-cyanoethyldodecylamine was 'acylated with acetyl chloride.

RNHCHzCHzCN CHaCOCl RITIOHzCHzCN COCHs R=C12H25 (2) The product of reaction #1 was hydrogenated.

In Step 1 of the above reaction, fl-cy'anoethyldodecylamine was allowed to react with acetyl chloride, the resulting N-acetyl, N-B-cyanoethyldodecylamine was hydrogenated over a nickel catalyst in the presence of catstic. The product of the second reaction, namely, acyl-N- dodecyl-1,3-propanediamine, was distilled in the presence, of copper chloride at 200 C. in vacuo to yield 3-dodecyl- Z-methyl-3,4,5,6-tetrahydropyrimidine. As an alternate to the third step described above, the substituted 1,3-propanediamine was distilled at a temperature of from 180- 200" C. at 0.1-0.15 mm. in the presence of Raney nickel to cyclize the substituted 1,3-propanediamine. The metal catalyst may also be packed in a heated column and the diamine run through the column to achieve cyclization. The use of the nickel or other metal catalyst as described above has been found to be very effective for ring closure reaction. Heretofore the ring closure has been effected only by extremely high temperatures, strong dehydrating agents, and long reaction times. We believe that the metallic ion may function as a chelating agent which 3 brings the amidoamine into the correct position for ring closure, e.'g.,

NHCH: t! M++ OH;

R O NH-CI-Iz GHQ- In the foregoing process, the alkyl acid halide employed in the acylation step may have from 1 to 22 carbon atoms. Any aliphatic or aromatic acylating agent, such 'as acid halides, anhydrides, etc., may be employed.

In Reaction 1, as set out above, an aryl substituent may be inserted into the tetrahydropyrimidine ring at the 2-position in place of the methyl group by using an aromatic acylating agent, such as benzoyl chloride, 3,4- dichlorobenzoyl chloride, mixed dichlorobenzoyl chlorides, alkylated benzoyl chlorides, etc., thus producing aryl and substituted aryl derivatives of tetrahydropyrimidines.

The preferred acylating agent is selected from the group consisting of alkyl and mono-carbocyclic aryl acid halides and anhydrides thus forming a diamine selected from the group consisting of alkanoyland mono-carbocyclic aroyl-N-aliphatic-1,3-propanediamine, respectively.

Reaction 2 above ordinarily yields two isomers shown as I and II. The isomers I and H are found to be about equally divided in a mixture when the hydrogenation is carried out at about 300 p.s.i. H pressure. Reductions at higher pressures, for example, at 800 psi, caused almost complete isomerization of isomer I to isomer II, In the case of the octyl and octadecyl derivatives, isomer II was found to exist to the extent of 93-98 percent. This phenomenon involves migration of the acetyl group 0 I] CIIHG" from one nitrogen group to the other during reduction.

The starting material used in the preparation of the tetrahydro pyrimidine may be prepared by the known proc ess of cyanoethylation of the desired amine. For example, dodecylamine may be reacted with a slight excess of acrylonitrile in the presence of about 4 percent water at 70 C. for a period of 2 to 3 hours. The product, cyanoethyldodecylamine, is obtained in almost quantitative yield.

DESCRIPTION OF THE PREFERRED EMBODI- MENTS A preferred embodiment of this invention is the process for preparing 3 aliphatic-2-substituted-3,4,5,6-tetrahydropyrimidine, the steps of reacting fl-cyanoethyl aliphatic amines having 8 to 22 carbon atoms with an acylating agent selected from the group consisting of alkyl and monocarbocyclic aryl acid halides and anhydrides, hydrogenating the reacted product over a nickel catalyst under pressure and in the presence of a base to produce an acyl-N-aliphatic 1,3-propanediamine, and heating the hydrogenated product in the presence of a catalyst selected from the group consisting of nickel, copper, cobalt, manganese, platinum, palladium, and the chloride, bromide, iodide, oxide, sulfate, carbonate, and acetate salts thereof, in the presence of a strong base at a temperature of about 170230 C. at subatmospheric pressure.

The third step may be carried out at subatmospheric pressure, usually in distillation, or the metallic catalyst may be packed in a heated column.

Specific examples illustrative of our processes and treatment methods may be set out as follows:

EXAMPLE r N-acetyl-N-fl-cyanoethyldodeeylarnine was prepared as follows:

A two-liter, three-nicked flask, equipped with mechanical stirrer, addition funnel, reflux condenser, and thermometer, was charged with cyanoethyldodecylamine (227 g., 0.95 mole), methylene chloride (1070 g.) and aqueous caustic (44 g. NaOH in ml. H O). The mixture was cooled to -5 C. and acetyl chloride (82.5 g., 1.05 mole) in 100 ml. CH Cl Was added slowly, with stirring over 7 045 minutes. The reaction temperature was maintained at 0 to -10 by external cooling. The mixture was stirred for an additional O.51.0 hour after the addition was completed. The aqueous caustic layer was separated, the organic layer dried over anhydrous sodium sulfate, and stripped at 2530 C.

The product was obtained as a pale yellow oil, 259.6 g. (96% yield) with an acid value of 6.9.

EXAMPLE II N-acetyl-N-(,E-cyanoethyl)dodecylamine was prepared as follows:

Acetic anhyride (26.7 g., 0.262 mole) was charged into the flask and the cyanoethyldodecylamine (67.5 g., 0.25 mole) added slowly with stirring. The temperature was maintained between 25 and 35 by external cooling and rate of addition of amine. One and a half hours were necessary for the addition. The reaction mixture was stirred for /2 hour after the addition was completed; after which excess acetic anhydride and acetic acid were removed under vacuum at 6085 C.

The crude product was obtained with a residual acid value of 21.

EXAMPLE III N-acetyl-N-dodecyl-1,3-propanediamine was prepared as follows:

A one-liter, stainless steel autoclave was charged with N-acetyl-N-cyanoethyldodecylamine (480 g., 1.71 moles), Raney nickel (9.6 g, 2% by weight alcohol washed), and tetraethyl ammonium hydroxide (TEAH, 2% by weight). The vessel was flushed with hydrogen and heated to C. Hydrogen was then added to a total pressure of 300 p.s.i.g. The temperature and pressure were maintained at 140 C. and 300 p.s.i.g. for 2.5 hours. The catalyst was removed by filtration to yield a pale yellow to while solid on cooling, 405 g. (83.5% yield).

Analysis.Sec.-amide, 44.4%

H NmonmNEo 0H3] EXAMPLE IV N-dodecyl-2-methyl-3,4,5,6 tetrahydropyrimidine was prepared as follows:

The reduction product of N-acetyl-N-cyanoethyldodecylamine (845 g., 2.97 moles) containing about 45% of N-acetyl-N-dodecyl-l,3-propanediamine and 39% N- acetyl-N-dodecyl 1,3 propanediamine was subjected to distillation over 1% by weight CuCl -2H O and 5 KOH pellets through a 12-inch Vigreux column. The material distilling at 164-180/0.l0.35 mm. was collected as a light yellow oil, 705 g. (89% yield).

Analysis.-NE, 252 (calcd. 266.5); PA, 5.3%; SA. 13.4%; TA, 81.5%.

EXAMPLE V N-acetyl-N-cyanoethyloctylamine was prepared as follows:

A five-liter, three-necked flask, equipped with a mechanical stirrer, addition funnel. reflux condenser, and thermometer, was charged with cyanoethyloctylamine (1,065 g., 5.4 moles). Acetic anhydride (612 g., 6.0

moles) was added slowly, with stirring, over a period of 90 minutes. The temperature of the reaction mixture was maintained at 23-28 C. by external cooling. The mixture was stirred for an additional hour after the addition was completed. The acetic acid liberated in the reaction was removed by stripping at 75 C. at 1 mm; Hg until the acid value dropped to 8.

The product was obtained as a pale yellow oil in almost quantitative yield, 1,261 g.

EXAMPLE VI N-acetyl-N'-octyl-1,3-propanediamine was prepared as follows:

A one-liter, stainless steel stirred autoclave was charged with N-acetyl-N-cyanoethyloctylamine (573 g., 2.56 moles) and Raney nickel catalyst (11.5 g. 2% by weight, alcohol washed). Ammonia was charged to a pressure of 125 p.s.i.g. at room temperature and the reaction mixture then heated to 130 C. Hydrogen was then added to a total pressure of 800 -p.s.i.g. The temperature and pressure were maintained at 130-l50 C. and 800 p.s.i.g. for 3-4 hours. The reaction product was filtered to remove the catalyst, then stripped under aspirator vacuum for 2 hours at 55 C.

The product was obtained as an amber oil in 98% yield, 573 g.

Analysis.-NE, 215 (calcd. 228); PA, 5.7%; SA, 93.5%; TA, 6.8%.

EXAMPLE VII N-octyl-2-methyl-3,4,5,6-tetrahydropyrimidine was prepared as follows:

N acetyl N'-octyl-1,3-propanediamine .(567 g., 2.49 moles) was subjected to distillation over 1% by weight CuCl -2H O (5.67 g.) and 3pellets KOH through a 12- inch Vigreux column. The material distilling at 130- 153 C./3-3.5 mm. was collected as a pale yellow oil (403 g., 77% yield).

Analysis.-NE, 204.8 (calcd. 210.3); TA, 87.4%.

EXAMPLE VIII N-acetyl-N-cyanoethyloctadecylamine was prepared as follows:

A five-liter, creased flask, equipped with mechanical stirrer, addition funnel, and thermometer, was charged with cyanoethyloctadecylamine (976 g., 3.04 moles) and one-liter of ether. Acetic anhydride (346.8 g., 3.4 moles) was added slowly, with stirring, over a period of one hour. The temperature of the reaction mixture was maintained at 25-30" C., by external cooling. A thick white solid was formed during the addition, requiring additional solvent to keep the mixture as a slurry. The mixture was stirred for an additional 40 minutes after the addition was complete. The reaction product was diluted with petroleum ether, cooled, and filtered to yield 845 g. (77.5% yield) of white solid, AV=3.

EXAMPLE IX N acetyl N octadecyl-1,3-propanediamine was prepared as follows:

A one-liter, stainless steel autoclave was charged with N acetyl N cyanoethyloctadecylamine (361.4 g., 0.99 mole) and Raney nickel (7.2 g. 2% by weight alcohol washed). Ammonia Was charged to a pressure of 125 p.s.i.g. at room temperature and the reaction mixture heated to 130 C. Hydrogen Was then added to a total pressure of 800 p.s.i.g. Temperature and pressure were maintained at 130 and 800 p.s.i.g. for 3.5-4 hours. The catalyst was removed by filtration and excess ammonia stipped under reduced pressure.

The product was obtained in almost quantitative yield.

Analysis.-NE, 362 (calcd. 368); PA, 4.4%; SA, 97.1%; TA, nil.

EXAMPLE X N octadecyl 2 methyl-3,4,5,6-tetrahydropyrimidine was prepared as follows:

N-acetyl-N-octadecyl-1,3-propanediamine (622 g., 1.69

EXAMPLE XI N-benzoyl-N-cyanoethyldidecylamine was prepared as follows:

N-l-cyanoethyldodecylamine (261.2 g., 1.09 moles), aqueous sodium hydroxide (51.4 g. in 117 ml. water) and 800 ml. of methylene chloride were charged into a fiveliter, three-necked flask. Benzo'yl chloride (150.9 g., 1.22 moles) was added slowly over sixty minutes at 5 C. The reaction mixture was then stirred for an additional ninety minutes at 5-10 C. The organic layer was separated, washed several times with water and dried over anhydrous sodium sulfate. Methylene chloride was distilled off under reduced pressure to yield 352 g. (94.4%) of product with a residual acid value of 4.1.

EXAMPLE XII Benzoyl-N-dodecyl-1,3-propanediamine Was prepared as follows:

A 300 ml., stainless steel stirred autoclave was charged with N-benzoyl-N-cyanoethyldodecylamine (162 g., 0.47 mole) and Raney nickel catalyst (16.2 g. 10% by weight alcohol washed). Ammonia was added to 150 p.s.i./ 30 C., then hydrogen to a total pressureof 400 p.s.i./ 30 C. The temperature was raised to C. and the total pressure increased to 2000 psi. with hydrogen. The reduction required 10-11 hours, yielding g. (92.5%) of crude benzoyl-N-dodecyl-1,3-propanediamine.

Analysis.Neut. equiv., 510 (calcd. 344 PA, 13.7%; SA, 42.6%; TA, 12.4%.

Infrared analysis shows no nitrile present.

The primary and secondary amine represents the two isomeric benzoyl N dodecyl 1,3 propanediamine. The tertiary amine is probably some tetrahydropyrimidine formed during the reduction. The high neutralization equivalent is due to the presence of a neutral material, probably N-dodecylbenzamide, formed by decyanoethylation of the starting material.

EXAMPLE XIII N dodecyl 2 phenyl 3,4,5,6 tetrahydropyrimidine was prepared as follows:

Crude benzoyl N dodecyl 1,3 propanediamine (141.0 g. containing about 20% dodecylbenzamide) was distilled over 1% CuCl and a trace of potassium hydroxide at -220 C./1 mm. to yield 86.8 g. of crude N- dodecyl 2 phenyl 3,4,5,6 tetrahydropyrimidine.

Analysis.Neut. equiv. 53-8 (calcd. 328), PA-I-SA =1.0%, TA=56.7% (as tetrahydropyrimidine).

The dodecylbenzamide in the above was removed by crystallization from Skellysolve B and the tetrahydropyrimidine thus obtained redistilled as above to give 50 g. (37.5% crude yield) of a yellow oil.

Analysis.Neut. equiv. 405 (calcd. 328), PA-I-SA 1.0%, TA =81.6%.

Infrared analysis indicated the product to be predominantly tetrahydropyrimidine with some monosubstituted amide present.

EXAMPLE XIV The catalyst eifect of the various materials was determined by distillation of the N acetyl N' dodecyl 1,3 propanediamine in the presence of the catalyst and determining the amount of tetrahydropyrimidine in the distillljte. This information is summarized in the following ta e:

Analysis before Analysis after distillation distillation Percent of Compound R= CnHn Catalyst change Pyrimidine distilled N.E Sec. Sec. N.E Sec. See.

amide amine amide amine Wet 1R II RNH(CHz) NHC CH None 100.7 95. 6 278 24.9 98. 6

i RNH CH2 3NHC OH; CuSO 100. 7 95. 6 287 64. 3 97 i RNH(CH)3NHCCH KOH 100.7 95.6 268 43. 5 43. 3 41. 5 48.4 96. 6

ll RNH(CH2) NHC CH CuSO KOH 287. 5 101.3 98 261 68.8 97

i RNH(CH)3NHC CH3 CoClzKOH 100. 7 95. 6 266. 5 24 21.8 59. 5 66. 6 90 RbIKCH CN Ni(R)KOH 308 61. 5 68. 4 266 68. 4 77. 9 ca. 80

O O O 11 Reduction product IR analysis shows primary amine. The reduction product consists of a mixture of 6% tetrahydropyrimidine and 76% EXAMPLE XV N (B cyanoethyl) N Isobutyldodecylamine was prepared as follows:

A one-liter, four-neck creased flask equipped with a mechanical stirrer, thermometer, addition funnel and reflux condenser was charged with 217 g. (0.80 mole) of N-(fl-cyanoethyl) dodecylamine. Isobutyric anhydride of a mixture of its corresponding isomer, to N dodecyl 2 methyl 3,4,5,6 tetrahydropyrimidine. In each case distillation was carried out using a 35-40 gm. charge over 1 wt. percent of the copper salt and 1-2 KOH pellets. Distillation temperatures were in the range of 170230 C./0.31.0

The starting material had the following analysis: NE

(139 g., 0.88 mole) was added at 23-30 C. over a 30 :286 TA minute period, then the reaction mixture stirred overnight at room temperature. The entire reaction mixture was dis- The results are Shown in the following tabla? solved in ether and washed seven times with water and aqueous KOH to remove any free acid. The ether was PREPARATION on N-DODECYL-2-METHYL-3,4,5,6- stripped off under reduced pressure and 249.2 g. (92% r TETRAHYDROPYRIMIDINE mass yield) of product was obtained, leaving an acid value of Catalyst Percent Percent Percent Percent Dlstilled TA 1 SA 2 PA 3 EXAMPLE XVI N (B cyanoethyl) N Isobutyryldodecylamine was ggg 'g-g 1-? gag reduced as follows: 1 1 A one-liter pressure reaction vessel was charged with 8110 245.8 g. of N (cyanoethyl) N isobutyryldodecylamine and 9.8 g. (4% by wt.) of alcohol washed Raney nickel catalyst. Ammonia was then added to 125 p.s.i.g. at room temperature and the temperature raised to 135 C. The total pressure was made up to 800 p.s.i.g. at 135 C., with hydrogen. The reaction temperature and pressure was maintained for two hours, then cooled and filtered to give 239.6 g. (97.2% mass yield) of product having the following analysis:

NE=254 (calcd. 314), PA=76.7%, SA=11.4%, TA =11.9%.

EXAMPLE XVII N dodecyl 2 isopropyl 3,4,5,6 tetrahydropyrirnidine was prepared as follows:

The reduction product obtained in Example XVI (231 g.) was distilled over 1% (by wt.) CuCl and 2-4 KOH pellets through a Claisen head distillation column. A fraction distilling at 170-193 C./1.02.4 mm. was obtained representing 124.6 g. or 51.9% of the charge having the following analysis: NE=237 (calcd. 256), TA=66.3%.

EXAMPLE XVIII Various copper salts were used as catalysts for cyclization of N dodecyl N acetyl 1,3-propanediamine, or

1 Terttiary amine represents the amount of tetrahydropyrimidine presen 2 Percent Secondary amine.

3 Percent Primary amine.

While in the foregoing specification we have set forth procedural steps and treating materials in considerable detail for the purpose of illustrating our invention, it will be understood that such detail or details may be varied widely by those skilled in the art without departing from the spirit of our invention.

We claim:

1. In a process for preparing tetrahydropyrimidines, the step of heating a compound selected from the group consisting of alkanoyland mono carbocyclic aroyl-N- aliphatic-1,3-propanediamine wherein the aliphatic group has from 8 to 22 carbon atoms in the presence of a catalyst selected from the group consisting of nickel, copper, cobalt, manganese, platinum, palladium, and the chloride, bromide, iodide, oxide, sulfate, carbonate, and acetate salts thereof, in the presence of a strong base at a temperature of about -230 C. at subatmospheric pressure.

2. The process of claim 1 wherein said diamine is selected from the group consisting of acetyland benzoyl- 5. The process of claim 1 wherein said base is selected N-aliphatic-1,3-propanediamine. from the group consisting of potassium hydroxide, sodium 3. The process of claim 1 wherein said catalyst is hydroxide and calcium hydroxide. present in from about 0.5 to 5 weight percent.

4. The process of claim 1 wherein said catalyst is 5 No references citedselected from the group consisting of copper chloride and Raney i kel, NICHOLAS S. RIZZO, Primary Examiner. 

